Hand-Foot Syndrome is a skin disease developed as a side effect of anti-cancer drug treatment and therefore is an indicator of the dose limiting factor of an anti-cancer drug. Favorite sites of Hand-Foot Syndrome are distal portions of the extremities, especially, the palms, soles, and nails and it often appears at these sites with erythema or pigmentation. Patients with mild symptoms (grade 1 of Hand-Foot Syndrome judging criteria) are not limited in the activities of daily living. However, in severe cases, patients develop swelling or redness with pain (grade 2 of said criteria). In addition, cornification or desquamation of the palms and soles become prominent, and sometimes a skin fissure develops, which is accompanied by hyperesthesia. Patients with such conditions might experience difficulty in holding things or in ambulation because of the pain (grade 3 of said criteria).
The pathogenic mechanism of Hand-Foot Syndrome is currently unexplained. For example, there are some factors, such as the inhibition of proliferating ability of cutaneous basal cell, the leakage of an anti-cancer drug from blood vessels (e.g., see Patent Document 1), or the secretion of an anti-cancer drug from the eccrine gland (e.g., see Nonpatent Document 1), which are suggested as one of the possible causes of Hand-Foot Syndrome. However, the causal connection between the pathogenesis of the same and an anti-cancer drug is yet unknown.
As mentioned above, the pathogenic mechanism of Hand-Foot Syndrome is unknown and therefore no prevention method or treatment method is established. the current treatment method of Hand-Foot Syndrome is mainly symptomatic treatment relying on empirical treatment such as: resting the limbs, or in the situation of severe swelling, cooling the limbs or elevating the limbs; a local treatment using an external formulation such as urea ointment, a heparinoid preparation or vitamin ointments for moisturizing purposes; a local treatment using a topical steroid with an anti-inflammatory effect; a systemic treatment using an internal remedy such as prednisolone, dexamethasone, or pyridoxine hydrochloride (Vitamin B6) (e.g., see Nonpatent Document 2); and for treatments of symptoms on the nail, washing, protecting with gauze, taping, onychoplasty, an artificial nail, cryosurgery, and so on.
In addition to the above, for example, the following treatments are also suggested: usage of local DMSO for the treatment of Hand-Foot Syndrome caused by liposomal doxorubicin (e.g., see Patent Document 1), usage of dihydropyrimidine dehydrogenase, thymidine phosphorylase, and/or an uridine phosphorylase enzyme inhibitor for the treatment of Hand-Foot Syndrome caused by fluorouracil or its precursor (e.g., see Patent Document 2), and usage of a cyclin-dependent kinase II inhibitor for prevention and/or reduction of severity of epithelial cytotoxicity side effects including Hand-Foot Syndrome caused by chemotherapy and/or radiation therapy (e.g., see Patent Document 3).
However, the effects of the aforementioned treatments are not satisfactory.
In addition, there are cases where the administration of responsible agents might have to be interrupted as there is no means to treat such symptoms. Nevertheless, for example, in a Phase 2 clinical study of capecitabine in Japan, it was reported that the period for recovery of Hand-Foot Syndrome for patients with the highest Hand-Foot Syndrome judging criteria grade of 3 after interruption is about two to three months on average (e.g., see Nonpatent Document 3), which shows the fact that it takes a long time for its recovery even with interruption.
Thus, a more effective drug product with instant results is demanded.
On the other hand, as for Hand-Foot Syndrome, there are some reports indicating the connectivity of its pathogenesis with sweat. For example, Patent Document 4 discloses an adhesive skin patch for patients under anti-cancer drug treatment, which contains an adhesive base, and at least one compound selected from the group consisting of oil, a polyhydric alcohol, and a hydrophilic high-molecular compound. It is described that the aforementioned skin adhesive patch is effective against Hand-Foot Syndrome by preventing sweat or sebum which contains such an anti-cancer drug to be stored in the skin and by absorbing sweat or sebum which contains the anti-cancer drug. However, this document focused on the fact that use of certain skin adhesive patches to remove the anti-cancer drug contained in the sweat or sebum is effective for Hand-Foot Syndrome. Furthermore, in this document, the anti-cancer drug that caused the pathogenesis of Hand-Foot Syndrome is not specified and this document does not describe which route of blood vessels and eccrine glands is important as a secretion pathway of the anti-cancer drug to the sweat or sebum.
On the other hand, it is described in Nonpatent Document 1 that the anti-cancer drug doxorubicin was detected in sweat from patients with Hand-Foot Syndrome who were administered with such a drug and that they were associated with hyperhidrosis, which implies the connectivity of Hand-Foot Syndrome with hyperhidrosis. However, it is not validated in this document the connectivity of the pathogenesis of Hand-Foot Syndrome with the drug substance in the sweat. This document suggests usage of an antiperspirant such as iontophoresis or aluminum chloride to suppress the pathogenesis of Hand-Foot Syndrome as the nature of this document is to associate Hand-Foot Syndrome with sweat. Although it has been five years since this document was published, it shows no successful experience of suppressing pathogenesis of Hand-Foot Syndrome using such antiperspirant.
Currently, the causal association between Hand-Foot Syndrome and the secretion of a drug substance into sweat is being questioned (e.g., see Nonpatent Document 4). It was described in this document that a drug substance was not detected in sweat from patients with Hand-Foot Syndrome caused by the anti-cancer drug sorafenib administration, and therefore there is no relationship between Hand-Foot Syndrome caused by sorafenib and the secretion of a drug substance in sweat. Finally, it concluded that further studies are needed to understand the mechanism of Hand-Foot Syndrome.
As mentioned above, the development of prevention and/or treatment methods of Hand-Foot Syndrome is essential and indispensable in order to continue anti-cancer therapy. However, no effective method has been established.